Psoriasis is a chronic condition that affects as much as 2.6% of the population of the developed world. A recent survey reported by the National Psoriasis Foundation estimates that 6.4 million people suffers from psoriasis, of which about 500,000 is rated as severe. The annual patient cost for treating psoriasis is currently estimated at $1.6 to $3.2 billion. Every year, about 400 people are granted disability by the Social Security Administration, and another 400 people die from psoriasis-related causes.
Characteristics of Psoriasis
It is not known what causes psoriasis, although there is evidence of a genetic predisposition and an autoimmune etiology. Onset may be triggered by systemic infections such as strep throat, skin injury, vaccinations, and certain oral medications such as steroids. Subsequently, the immune system is thought to induce inflammation and excessive skin cell reproduction, which can be exacerbated by additional factors such as stress and diet.
In normal skin, the time for a cell to move from the basal layer through the granular layer is 4-5 weeks. In psoriatic lesions, the time is decreased 7-10 fold because of a shortened cell cycle time, an increase in the absolute number of cells capable of proliferating, and an increased rate of division. T cell mediated immune responses appear to be responsible for the inflammation and hyperproliferation of keratinocytes. Neutrophils are found in psoriatic lesions, associated with increased levels of plasminogen activator. Psoriatic fibroblasts have increased levels of enzymes involved in collagen synthesis, secondary to expansion of the papillary dermis. Psoriatic plaques comprise HLA-DR positive keratinocytes and Langerhans cells, and activated T cells expressing elevated levels of IL-2 receptors.
The typical lesion of psoriasis is a well-demarcated erythematous plaque, covered by thick, silvery scales. Psoriasis can become so extensive as to cause exfoliative erythroderma, in which the entire epidermal surface is in a state of hyperproliferation. Gluttate psoriasis is a form of the disease following streptococcal pharyngitis, with widely distributed characteristic 1-3 cm lesions. Pustular psoriasis is characterized by numerous sterile pustules of 2-5 mm in diameter, and may lead to an acute, explosive, life-threatening episode of fever, chills, leukocytosis, hypoalbuminemia, and hypocalcemia, demanding immediate, vigorous therapy. Previously stable plaque-type psoriasis can be acutely exacerbated by viral infections, particularly HIV. Psoriasis is also associated with five different forms of psoriatic arthritis, including distal interpharangeal involvement; an asymmetric, oligoarticular pattern; a symmetric polyarthritis; arthritis mutilans; and sacroiliitis and spondylitis.
The inflammation and hyperproliferation of psoriatic tissue is associated with a different histological and antigenic profile than normal skin. Dabelsteen et al. used a panel of anti-carbohydrate monoclonal antibodies to compare psoriatic tissue with the surrounding dermis. The glycosylation pattern in psoriatic epithelium is changed in two ways: some carbohydrates are expressed at an earlier stage of cell maturation. In addition, certain biosynthetic precursor antigens not expressed in normal skin were found in psoriatic skin.
Paller et al. (1989) investigated the distribution of ganglioside GM3 using an antibody designated 8G9D8. At the electron microscope level, antibody deposition was seen in the corneocyte envelope. Disposition was significantly decreased or absent in disorders of excessive keratinocyte proliferation, including squamous cell carcinomas, congenital ichthysiform erythrodermas, prokeratosis, and psoriasis. In a subsequent study, Paller et al. (1993) found that when GM3 was added to keratinocytes from normal foreskin, lesional skin from patients with psoriasis or ichthyosis, and to cutaneous squamous carcinoma lines, it inhibited growth in a dose-dependent manner at concentrations of 10-100 xcexcM. Confluent undifferentiated keratinocytes were least sensitive. The gangliosides GD3, 9-O-acetyl-GD2, and GD1b also inhibited keratinocyte proliferation. Gangliosides GM1 and GD1a, and sialic acid had little effect. The authors concluded that preferential activation of sialyltransferase II may be involved in control of keratinocyte growth, but not differentiation.
Concharenko et al. studied ganglioside expression on the erythrocytes and serum of healthy subjects, and patients with psoriasis. During phases of exacerbation, a marked decrease was observed in the content of GM2 and GM3 fractions of the red cells, and GD1a decreased in serum. The presence of a new monosialoganglioside fraction was noted during exacerbation, both in serum and on red cells. The ganglioside spectrum of patients in clinical remission of psoriasis was almost normal.
Heidenheim et al. describe a monoclonal antibody designated UM4D4 which recognizes the cell surface marker CDw60. This marker is present on a subset of normal T cells, melanocytes, malignant melanoma cells, and hyperproliferative psoriatic keratinocytes. CDw60 antibodies bind to the acetylated form of GD3. 74% of basal cell carcinomas express CDw60, whereas CDw50 expression in normal skin is confined to melanocytes and a few scattered keratinocytes at the basal cell layer. Skov et al. recently reported that in psoriatic skin, basal and suprabasal keratinocytes express CDw60. Cloned T cell lines obtained from lesional skin upon initiation were found to release a cocktail of soluble factors including IL-4 and IL-13, that up-regulated CDw60 expression on cultured normal keratinocytes.
Currently Available Treatments for Psoriasis
Classical treatments of psoriasis include calciptriene (a vitamin D3 derivative), topical coal tar preparations, systemic antimitotic agents such as methotrexate, and retinoids, particularly etretinate. Extensive psoriasis can be treated by photosensitization with oral 8-methoxypsoralen, followed by ultraviolet A. Corticosteroids are given for psoriatic arthritis and acute attacks of pustular psoriasis. More recently, cyclosporin A has been tested in clinical trials at doses of 3-7 mg/kg with promising results, but associated with the risk of renal toxicity. There is no cure.
Current biotechnology approaches to psoriasis treatment relate to a direct pharmaceutical-mediated attack, either on cell proliferation or on the immune component of the disease. Japanese patent application JP 6145069 describes angiogenesis inhibitors comprising ganglioside GM3 or a GM3 analog as an active agent. At 100 xcexcg/mL, GM3 showed growth of normal human antioendothelial cells of 4.5xc3x97104 on day 5, compared with 76xc3x97104 in controls. U.S. Pat. No. 5,339,977 describes n-deacetyl-lysoganglioside derivatives for use as phospholipase A2 inhibitors for the treatment of proliferative and autoimmune diseases, including various forms of cancer, psoriasis, and rheumatoid arthritis.
An IL-2 fusion toxin has been developed (Seragen, Inc.) that is designed to selectively destroy activated T cells in psoriatic plaques, leaving normal cells alone. The objective is to destroy activated T cells, and thereby clear the psoriasis. A Phase II study has been performed in which test doses of 5, 10, and 15 xcexcg/kg were administered per day. Comparable improvement was observed in patients with moderate to severe psoriasis. However, in order to obtain this response, the compound was administered three days per week for four weeks.
Various formulations containing the compound BCX-34 for psoriasis, cutaneous T cell lymphoma, and HIV infection have been tested (Bioworld Today, Sep. 29, 1997; see also WO 95/01355; WO 93/21187; WO 90/10631; U.S. Pat. Nos. 5,008,270, 5,008,265, and 4,985,434). BCX-34 is a small molecule drug that inhibits purine nucleoside phosphorylase, a human enzyme believed to be involved in the proliferation of T cells. An oral formulation is being tested in an ongoing Phase I/II trial. A topical formulation advanced to the Phase III stage for both lymphoma and psoriasis. The Phase III psoriasis study showed only a 14% greater improvement in mean lesion scores in the treated group compared to placebos, which for these studies was not statistically significant.
Accordingly, there is a need for therapeutic compositions that are effective in managing psoriasis, particularly if they are effective when given on an occasional basis. The present invention relates to a strategy in which the patient""s own immune system is recruited into an active role against the disease.
The invention provides methods of using compositions which elicit an immune response against an antigen that is aberrantly expressed in psoriatic tissue.
Accordingly, in one aspect, the invention provides methods for treating psoriasis in an individual, comprising administering a composition effective in stimulating a specific immunological response against an antigen aberrantly expressed in human psoriatic tissue. These composition(s) comprise an antigen that shares immunological characteristics of an antigen that is aberrantly expressed in psoriatic tissue (such as human psoriatic tissue). Antigens aberrantly expressed in psoriasis include but are not limited to gangliosides. While a detectable immunological response is likely to be beneficial, efficacy can also be deduced by an improvement in symptoms or control of the psoriatic condition beyond what would be expected without treatment.
Certain embodiments of the invention include methods for treating psoriasis in an individual by eliciting an anti-ganglioside immunological response in the subject. The immunological response can be elicited using any suitable immunogen and/or immunogenic composition, such as: (1) a ganglioside in an immunogenic form, such as GM2, GM3, GD1b, GD2, 9-O-acetyl GD2, GD3, GD3 lactone, 9-O-acetyl GD3, and GT3; (2) an anti-idiotype for a ganglioside, such as the monoclonal antibodies 1A7, 4B5, or BEC-2; or (3) a polynucleotide encoding an anti-idiotype for a ganglioside. The immunological response can have humoral or cellular components, and preferably has both.
Further embodiments of the invention relate to preparing a composition for use in the treatment of psoriasis by preparing a composition comprising the determinant in an immunogenic form, or else raising an anti-idiotype against a monoclonal antibody that binds the antigenic determinant. Also embodied are methods for screening a composition for efficacy in treating psoriasis, involving administering the composition to human subjects, and monitoring disease progression (optionally in combination with immunological parameters) following treatment.
A further embodiment of the invention is a composition containing a ganglioside, an anti-idiotype for a ganglioside, or a polynucleotide encoding a ganglioside, packaged with an indication of its suitability for use in treating psoriasis.
Further embodiments of the invention relate to the use of a component selected from the group consisting of a ganglioside, an anti-idiotype for a ganglioside, and an expression vector encoding an anti-idiotype for a ganglioside, in the manufacture of a medicament for the treatment of psoriasis.